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The notion of "independent clans" is one that only dates back to the formation of the Camarilla; in the Dark Medieval era before the rise of the modern sects, the only distinction between clans was that between the High and Low Clans. The four original independent clans in publication history were described as the Giovanni, the Followers of Set, the Assamite, and the Ravnos. During the modern nights, the Gangrel have declared independence as well, its elders having formally severed the clan's ties with the Camarilla.

Each clan's reason for independence varies: in the case of the Assamites and Giovanni, there are specific deals with the Camarilla that guarantee autonomy. The Followers of Set just weren't interested, and the Ravnos never participated in any party they could not crash first. Each clan also has certain eccentricities that separate them from the mainstream of Cainite culture - the Followers of Set, Ravnos, and Assamites all view Cainite vampires with a certain degree of disdain, and the Ravnos and Assamites in the West are effectively tips of an iceberg. There are far more Ravnos and Assamite vampires in their home territory and their structure is more complex there, not least because of a relative lack of Cainite competition in the area. As for the Giovanni, their goals are largely orthogonal to Cainite society and they are just as happy to be left alone. Finally, the Gangrel left the Camarilla over concerns that the sect was ignoring threats to their very existence: specifically, a creature that they believed to be an Antediluvian.

Despite their independence, most of these clans are willing to work with the sects, or at least within their territories, within reason. Most Gangrel retain some ties to the sect before the clan broke away. The Giovanni have seen their business with the Ivory Tower increase since the two worked together to retake the cities of New York and Boston. Finally, a large faction of schismatic Assamites has allied itself with the Camarilla since the MethuselahUr-Shulgi arose and began purging those who did not renounce all faiths other than the Path of Blood.

The independent clans were introduced in the first edition The Players Guide and have been expanded since. In first edition, each clan had a novel clan discipline (the first actual clan disciplines); later editions added clan-specific Paths of Enlightenment as well.